Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1.
Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1.
复制标题
DOI：
10.1038/srep17376
复制
发表时间：
2015-11-27
影响因子：
4.6
通讯作者：
Hara S
中科院分区：
文献类型：
--
作者：
Sasaki Y;Kamiyama S;Kamiyama A;Matsumoto K;Akatsu M;Nakatani Y;Kuwata H;Ishikawa Y;Ishii T;Yokoyama C;Hara S
前列环素合成酶(PGIS)和微粒体前列腺素E合成酶-1(mPGES-1)是前列腺素(PG)末端合酶，分别位于可诱导的环氧合酶(COX)-2下游，在PGI2和PGE2生物合成途径中发挥作用。已发现mPGES-1参与多种COX-2相关疾病，如炎症性疾病、癌症等，但目前尚不清楚PGES-1如何参与这些COX-2相关疾病。在这里，为了阐明PGIs的病理生理作用，我们研究了PGIs和mPGES-1单独基因敲除(KO)或双基因敲除(DKO)小鼠的表型。结果表明，硫代乙醇酸盐诱导的白细胞渗入腹膜腔的作用受到PGIs基因缺失的抑制。在PGIS KO小鼠中，脂多糖诱导的痛觉伤害(通过醋酸诱导的扭体反应进行评估)也减少了。在PGIS/mPGES-1 DKO小鼠中，这两种反应都比在PGIS KO小鼠中更有效地被抑制。另一方面，与mPGES-1缺乏(抑制偶氮甲烷诱导的结肠癌)不同，PGIS缺乏在癌变早期上调异常隐窝病灶的形成，在晚期上调息肉形成。这些结果表明，PGIs和mPGES-1协同加重炎症反应，但对致癌有相反的作用，而PGIs衍生的PGI2具有抗癌作用。
Prostacyclin synthase (PGIS) and microsomal prostaglandin E synthase-1 (mPGES-1) are prostaglandin (PG) terminal synthases that function downstream of inducible cyclooxygenase (COX)-2 in the PGI2 and PGE2 biosynthetic pathways, respectively. mPGES-1 has been shown to be involved in various COX-2-related diseases such as inflammatory diseases and cancers, but it is not yet known how PGIS is involved in these COX-2-related diseases. Here, to clarify the pathophysiological role of PGIS, we investigated the phenotypes of PGIS and mPGES-1 individual knockout (KO) or double KO (DKO) mice. The results indicate that a thioglycollate-induced exudation of leukocytes into the peritoneal cavity was suppressed by the genetic-deletion of PGIS. In the PGIS KO mice, lipopolysaccharide-primed pain nociception (as assessed by the acetic acid-induced writhing reaction) was also reduced. Both of these reactions were suppressed more effectively in the PGIS/mPGES-1 DKO mice than in the PGIS KO mice. On the other hand, unlike mPGES-1 deficiency (which suppressed azoxymethane-induced colon carcinogenesis), PGIS deficiency up-regulated both aberrant crypt foci formation at the early stage of carcinogenesis and polyp formation at the late stage. These results indicate that PGIS and mPGES-1 cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis, and that PGIS-derived PGI2 has anti-carcinogenic effects.